Autoimmune diseases are thought to result from breaks in tolerance, brought upon by abnormalities in the recognition of exogenous or endogenous antigens. A network of cellular and molecular mechanisms constantly adjusts the immune response within the limits of tolerance for self-antigens. Recently, regulatory T cells (Treg) have been recognized as essential in maintaining tolerance, and in re-establishing immune homeostasis. In spite of recent efforts, many unanswered questions remain however, particularly regarding the nature of cells/factors/mechanisms that control the generation and/or activity of antigen-specific Treg. Neuroimmune interactions between the CNS and the immune system are mediated through soluble factors such as cytokines, chemokines, neuropeptides, and neurotransmitters. Although a large number of studies attest to the role of neuropeptides as immunomodulators, the question whether they contribute to the generation and/or activation of Treg has not been addressed. We reported previously on the potent anti-inflammatory effect of the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) both in vivo and in vitro. The central hypothesis of this proposal is that VIP and PACAP induce the generation and/or activation of Treg, which then play an essential role in implementing the VIP/PACAP anti-inflammatory functions. In the first two specific aims, we propose to investigate the generation and/or activation of Treg by VIP/PACAP in vivo and in vitro, to characterize the VIP/PACAP-induced Treg in terms of phenotype, antigen-specificity, and mechanisms for suppression, and to evaluate the role of dendritic cells in the induction of Treg by VIP/PACAP. In the third specific aim, we propose to extend our investigation into two models of Th1-dominated autoimmune diseases. We will evaluate the role of Treg in the protective effect of VIP/PACAP in EAE and collagen-induced arthritis, with the ultimate goal of establishing new therapeutic avenues for the treatment of autoimmune diseases.